Prognostic Impact of t(1;19) in Pediatric B-Cell Acute Lymphoblastic Leukemia (B-ALL) Patients Treated on Contemporary Children's Oncology Group (COG) Protocols
Notice bibliographique
Résumé
Background Translocation t(1;19)(q23;p13.3) resulting in the TCF3::PBX1 fusion is a recurrent cytogenetic alteration in 5-7% of B-cell acute lymphoblastic leukemia (B-ALL) that occurs more frequently in Black children. Historically, t(1;19) was associated with inferior outcomes with higher rates of central nervous system (CNS) relapse; contemporary prognostic impact is unclear. We assessed t(1;19) outcomes with modern Children's Oncology Group (COG) therapy. Methods From 2010 to 2019, children and young adults with newly diagnosed B-ALL enrolled on standard risk (SR)(AALL0932; NCT01190930) or high risk (HR) (AALL1131; NCT02883049) protocols based on initial white blood cell count (WBC), age, extramedullary disease status, cytogenetic subtype, day 8 peripheral blood and end of induction (EOI) bone marrow flow cytometric minimal residual disease (MRD). Cytogenetic alterations were classified as favorable (ETV6::RUNX1 or double trisomies of chromosomes 4 and 10), unfavorable (iAMP21, KMT2A rearrangement, hypodiploidy) or neutral (all others). The t(1;19), detected by metaphase karyotyping and confirmed by central review, was considered a neutral cytogenetic lesion not impacting risk stratification. Patients 1-10 years of age with WBC <50,000/uL without unfavorable cytogenetics, CNS3 or testicular disease and EOI marrow MRD <0.01% were treated on AALL0932 while NCI HR (age ≥10 years and/or WBC ≥50,000/uL) and any patients with unfavorable cytogenetics, EOI MRD ≥0.01% and/or CNS3 or testicular leukemia or steroid pretreatment were treated on AALL1131. Patients with Down syndrome or Philadelphia chromosome-positive B-ALL were excluded from this analysis. Results Among 6417 patients 1-31 years, 270 (4.2%) had t(1;19) by karyotype, including 90 (33%) and 180 (67%) with a balanced and unbalanced translocation, respectively. The t(1;19) was associated with age ≥ 10 years, female sex, WBC ≥ 50,000/µL, CNS2/3 disease, Black race or Hispanic ethnicity, and Day 29 MRD < 0.01%. The 5-year (yr) disease-free (DFS) and overall survival (OS) for all patients with and without t(1;19) were not significantly different (DFS 92.1% ± 1.8% vs 91.2% ± 0.4%, P =0.39; OS 95.1% ± 1.4% vs 96.4% ± 0.3%, P=0.46) and there were no significant differences between balanced or unbalanced translocations (DFS 91.0% ± 3.2% vs 92.6% ± 2.1%, P = 0.61; OS 94.4% ± 2.6% vs 95.5% ± 1.7%, P=0.69). When separately analyzing 5-yr DFS and OS among NCI SR and NCI HR patients with and without t(1;19), there were similarly no significant differences [NCI SR: DFS 96.8% ± 1.6% vs. 94.0% ± 0.4%, P=0.11 and OS 97.6% ± 1.4%, vs. 98.3% ± 0.2%, P=0.78; NCI HR: DFS 87.7% ± 3.0% vs. 83.4% ± 1.0%, P=0.14 and OS 92.8%±2.3% vs. 90.9% ± 0.8%, P=0.35]. When compared to other patients with neutral cytogenetics, patients with t(1;19) had improved 5-yr DFS and similar OS (DFS 92.1% ± 1.8% vs 87.2% ± 0.7%, P = 0.01; OS 95.1% ± 1.4% vs 94.6% ± 0.5%, P = 0.853). Notably, NCI SR patients with t(1;19) fared as well as those with favorable cytogenetics (DFS 96.8% ± 1.6% vs 95.9% ± 0.4%, P = 0.34, OS 97.6% ± 1.4% vs 98.9% ± 0.2%, P = 0.37). Relapses occurred in 16 (5.9%) patients with t(1;19) compared to 480 (7.8%) without t(1;19) with a similar percentage of isolated CNS relapses (1.9% vs 1.7%), respectively. In a multivariable Cox regression model adjusted for other disease related variables, t(1;19) was significantly associated with decreased risk vs. unfavorable cytogenetics (hazard ratio 0.25, 95% CI: 0.15-0.41, P <.001) and other neutral cytogenetics (hazard ratio 0.62, 95% CI: 0.40-0.97, P = 0.04); and was not statistically significantly different than favorable cytogenetics outcomes (hazard ratio 1.27, 95% CI: 0.79-1.98, P = 0.33). Conclusions With contemporary therapy, t(1;19) did not confer an inferior prognosis overall. Notably, patients with t(1;19) had improved DFS and OS compared to those with other neutral cytogenetics and, among the NCI SR group, fared as well as those with favorable cytogenetics. T(1;19) did not confer an increase in CNS relapse. Our data support that patients with t(1;19) do not need therapy intensification when treated on contemporary risk-directed COG regimens.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».